Dental caries is the most common infectious disease of humans. The main causative agent is a group of streptococcal species collectively described as the mutans streptococci (Balakrishnan, et al. (2000) Aust. Dent. J. 45:235-45). Streptococcus mutans has been identified as the major etiological agent of the disease. Unlike many other diseases, dental caries is as prevalent in the West as it is in developing countries, and therefore attracts significant interest from medical and dental authorities as well as pharmaceutical companies. The first step in the initiation of infection is the attachment of the bacterium to a suitable receptor; an ideal point for intervention. Two groups of proteins from mutans streptococci represent primary candidates for a human caries vaccine: glucosyltransferase enzymes, which synthesize adhesive glycans and allow microbial accumulation; and cell surface fibrillar proteins that mediate adherence to the salivary pellicle (Hajishengallis and Michalek (1999) Oral Microbiol. Immunol. 14:1-20). The bacterial adhesin SAI/II (Russell, et al. (1978) Arch. Oral Biol. 23:7-15), a surface-displayed protein with a molecular mass of 190 kDa, plays an important role in the initial attachment of Streptococcus mutans to the tooth surface.
The murine monoclonal antibody Guy's 13 (Smith and Lehner (1989) Oral Microbiol. Immunol. 4:153-8) which specifically recognizes the SAI/II protein of Streptococcus mutans and Streptococcus sobrinus (Smith and Lehner (1989) supra) has been used successfully to prevent Streptococcus mutans colonization and the development of dental caries in non-human primates (Lehner, et al. (1985) Infect. Immun. 50:796-9). The antibody also prevented bacterial colonization in human clinical trials (Ma, et al. (1990) Infect. Immun. 58:3407-14; Ma, et al. (1989) Clin. Exp. Immunol. 77:331-7). However, like other murine antibodies, a major limitation in clinical applications may be the human anti-mouse antibody response (HAMA), which can increase the rate of clearance and initiate allergic reactions (Saleh, et al. (1990) Cancer Immunol. Immunother. 32:185-90). The problems associated with murine antibodies can be overcome by replacing murine sequences with their human counterparts, e.g., by chimerization (Mountain and Adair (1992) Biotechnol. Genet. Eng. Rev. 10:1-142), CDR grafting (Kettleborough, et al. (1991) Protein Eng. 4:773-83) and guided selection using phage display technology (Beiboer, et al. (2000) J. Mol. Biol. 296:833-49). Furthermore, the use of antibody fragments rather than whole antibodies also removes some of the constant regions that may provoke an immune response.
Anti-SAI/II antibodies and fragments thereof have been disclosed in U.S. Pat. Nos. 5,518,721; 5,612,031; and 5,854,402 and WO 88/06455. These disclosures teach combating dental caries using an anti-SAI/II antibody composition in the form of a toothpaste, mouthwash, chewing gum, lozenge or gel.
However, and despite the fact that several potential therapies to combat dental caries using an anti-SAI/II antibody have been taught, the production and existence of engineered human diabodies which overcome problems associated with conventional antibodies and which can efficiently be used to treat dental caries have not been identified.